Osteoarthritis (OA) is a degenerative joint disease that is the leading cause of disability in the elderly population. Concomitant structural and functional alterations in cartilage and underlying subchondral bone are central contributing factors to OA development, but the specific role of subchondral bone in OA pathology remains unclear. Determining the role of intrinsic subchondral properties prior to disease initiation and subchondral bone remodeling during OA progression is critical to better understanding disease mechanisms and developing diseasemodifying therapies.

To determine whether natural variability in intrinsic subchondral bone mass was predictive of load-induced OA severity, we pooled data from the C57Bl/6 mice in previously published load-induced OA studies and performed regression analyses to examine the relationship between intrinsic subchondral bone mass and load-induced OA development. Intrinsic subchondral bone mass negatively correlated to load-induced OA severity, indicating low intrinsic bone mass may increase load-induced OA susceptibility or progression.

To further examine the role of low intrinsic subchondral bone mass in OA pathology, we used osteoblast-specific estrogen receptor-alpha knock-out (pOC-ERαKO) mice, previously determined to develop osteopenia resulting from impaired estrogen signaling in bone. Following cyclic loading to initiate OA development, pOC-ERαKO mice with low subchondral bone mass developed more severe OA than littermate controls with normal bone mass.

Next, we used parathyroid hormone (PTH) to increase subchondral bone mass prior to OA initiation through daily cyclic loading and alendronate to inhibit subchondral bone remodeling during OA progression. PTH increased pre-disease subchondral bone mass, directly improved cartilage health, and slowed the development of OA pathology. Inhibiting bone remodeling with alendronate attenuated OA-related changes in subchondral bone.

Finally, to examine the role of early stage alterations in subchondral bone remodeling following post-traumatic OA development, we inhibited remodeling with alendronate starting at multiple time-points following a single bout of loading. Inhibiting remodeling immediately after loading most effectively attenuated the development of OA pathology in both cartilage and bone.

In summary, this thesis improves our understanding of the role of subchondral bone in OA development and progression, and suggests the potential of subchondral bone as a target for OA preventative strategies and disease modifying therapies.